The understanding and treatment of age-related macular degeneration (AMD), the leading cause of blindness in the developed world, is undergoing a revolution. Intraocular injections of medications that can arrest the rapidly destructive wet form of the disease have changed this form to a chronic, manageable illness. Now we are facing the challenge of the dry, or atrophic, form of AMD that proceeds more slowly but whose progression to the advanced form of geographic atrophy (GA) is at best impeded, but not stopped, by current therapies of oral antioxidants. The broad goal of this research is a better and unified understanding of the biochemical and structural components of dry AMD, in the living eye and validated in the laboratory, that in turn will lead to the root causs and treatment. Theories of the pathogenesis of dry AMD and GA abound, but none are certain. One thread common to many involves the retinal pigment epithelium (RPE), an important layer of cells just under the retina that are critical to its nutrition, oxygen supply, and visual functins. Hence, it is logical that RPE health may play a role in AMD. Fortunately, there is a non-invasive imaging technique with which to study the RPE called autofluorescence (AF), which is gaining in use in clinical and research settings. The basic principle is that the RPE contains a substance called lipofuscin which fluoresces under blue light to produce an orange glow that can be detected and mapped. Very recently, the imaging instrument has been modified for research by inserting a fluorescent reference chip that allows the AF signal to be quantified (qAF imaging), thereby providing a biochemical assay of the amounts and distribution of lipofuscin. Hence, these quantities and patterns can be directly compared, between normal subjects and patients with AMD, and across time. In particular, these images are excellent pictures of the RPE in the early stages of dry AMD and as these stages progress to GA. Another rapidly advancing technology is called spectral domain optical coherence tomography (SD- OCT). It provides high-resolution structural images of the living retina, RPE, and underlying choroid. The specific aims of this proposal consist of harnessing together the biochemistry of qAF and the structural precision of SD-OCT to understand the interaction of the RPE and retina as AMD progresses over time. Gifted collaborators in the pathology lab will guide study efforts with parallel studiesof donor eyes with the same stages of AMD, by identifying the exact anatomical structures seen in images of living patients. Success in this venture will bring much-needed relief to suffering patients and relief to the healthcare burden of an aging population.